Background and objectives In the present article, we explore a novel strategy of selenium nanoparticles (Se-NPs) for the treatment of type 2 diabetes mellitus (T2DM) by investigating the effect of Se-NPs alone and in combination with standard anti-diabetic drug metformin (MET) in high-fat diet/streptozotocin (HFD/STZ)-induced T2DM. Methods HFD was supplemented daily to experimental rats for 8 weeks, followed by a single low dose injection of 35 mg/kg of STZ to induce T2DM. The synergistic effect of the different therapeutic strategies on diabetic complications was evaluated after the Se-NPs and MET administration for 8 weeks. Molecular and biochemical analyses were conducted to figure out the effectiveness of our treatment on insulin sensitivity, oxidative mediators and inflammatory markers. Results Our observations demonstrated that HFD/STZ-induced rats have a toxic effect on serum and hepatic tissues resulted in inducing remarkable oxidative damage and hyper-inflammation with a significant disturbance in the insulin signaling pathway. Experimental animals either treated with mono-therapeutic-two doses Se-NPs (0.1 and 0.4 mg/kg) and/or MET (100 mg/kg) alone as well as the combined therapy resulted in a remarkable protective anti-diabetic effect illustrated by significant decreases in fasting blood glucose and insulin levels after 8 weeks treatment. At the same time, the levels of active insulin signaling proteins pIRS1/pAKT/pGSK-3β/pAMPK were significantly improved. Moreover, Se-NPs exhibited an anti-inflammatory effect by the mitigation of cytokine expression and a balance between oxidative stress and antioxidant status was restored. Furthermore, the anti-diabetic drug MET administration also exhibited a significant improvement in diabetic complications after the treatment period. Conclusion This study provides mightily the mechanism of action of combined Se-NPs and MET as a promising therapeutic alternative that synergistically alleviates most of diabetic complications and insulin resistance.

The black cumin (Nigella sativa) “NS” or the black seeds have many pharmacological activities such as antioxidant, anticarcinogenic, antihypertensive, and antidiabetic properties. In this work, streptozotocin-induced diabetic rats fed with a high-fat diet were treated daily with NS oil (NSO) in order to study the effect on the blood glucose, lipid profile, oxidative stress parameters, and the gene expression of some insulin receptor-induced signaling molecules. This treatment was combined also with some drugs (metformin and glimepiride) and the insulin receptor inhibitor I-OMe-AG538. The administration of NSO significantly induced the gene expression of insulin receptor compared to rats that did not receive NSO. Also, it upregulated the expression of insulin-like growth factor-1 and phosphoinositide-3 kinase, whereas the expression of ADAM-17 was downregulated. The expression of ADAM-17 is corroborated by the analysis of TIMP-3 content. In addition, the NSO significantly reduced blood glucose level, components of the lipid profile, oxidative stress parameters, serum insulin/insulin receptor ratio, and the tumor necrosis factor-α, confirming that NSO has an antidiabetic activity. Thus, the daily NSO treatment in our rat model indicates that NSO has a potential in the management of diabetes as well as improvement of insulin-induced signaling.

Background and objectivesInsulin resistance of the brain is a specific form of type2-diabetes mellitus (T2DM) and the active insulin-signaling pathway plays a neuroprotective role against damaging conditions and Alzheimer’s progression. The present study identifies the mediated emerging effects of the Nigella sativa oil (NSO) on the memory enhancing process, its anti-oxidative, acetylcholinestrase (AChE) inhibition, anti-brain insulin resistance and anti-amyloidogenic activities. In addition, the possible role of some anti-diabetic drugs in the neuro-protection processes and their effect in combination with NSO and/or the insulin receptor inhibitor IOMe-AG538 were investigated.MethodsT2DM-induced rats were orally and daily administrated 2.0 ml NSO, 100 mg metformin (MT), 0.8 mg glimepiride (GI) and different combinations (100 mg MT & 2.0 ml NSO, 0.8 mg GI & 2.0 ml NSO and 2.0 ml NSO & intraperitoneal injection of 1/100 LD50 of IOMe-AG538) per kg body weight for 21 days.ResultsA significant increase in the brain lipid peroxidation and decrease in the antioxidant status with peripheral and central production of pro-inflammatory mediators were observed in diabetes-induced rats. The brain AChE was activated and associated with diminished brain glucose level and cholinergic function. In addition, the brain insulin resistance and the attenuated insulin signaling pathway (p-IRS/ p-AKT/p-GSK-3β) were accompanied by an augmentation in GSK-3β level, which in turn may contribute in the extensive alterations of Tau phosphorylation along with changes in PP2A level. Furthermore, neuronal loss and elevation in Aβ-42 plaque formation were observed due to a low IDE formation and an increased expression of p53, BACE1 and APP with diminished ADAM10, SIRT1 and BDNF levels. The expression profile of AD-related miRNAs in sera and brain tissues displayed its neuro-protection role. The treatment of diabetes-induced rats with NSO and the anti-diabetic drugs alone and/or in combination have the potential to suppress the oxidative stress, the pro-inflammatory mediators and amyloidogenic pathway. Moreover, it lowers the insulin receptor inhibitory effect of IOMe-AG538 and modifies the insulin-signaling pathway. Therefore, it prevents the neurotoxicity, amyloid plaque formation and Tau hyper-phosphorylation and restores AD-related miRNA normal levels.ConclusionThese data suggest that NSO or its combined treatments with anti-diabetic drugs have a possible benefit as disease modifying agents for the insulin resistance in the brain through enhancing brain insulin signaling pathway.

N-nitrosamines are widely spread environmental pollutants of well-known toxicity and carcinogenicity in various animal species. These compounds are metabolically activated by cytochrome P450 system predominantly in the liver and in other tissues into more active metabolites leading to generation of both alkylating agents that alkylate DNA and reactive oxygen species. In the current study, we investigated the influence of four types of N-nitrosamines that are commonly present in the environment [methyethylnitrosamine, (MEN), diethylnitrosamine (DEN), diphenylnitroasamine (DPN) and dimethylnitrosamine (DMN)] on both livers and testes of male rabbits through assessment of 17 β-hydroxysteroid dehydrogenase (17 β-HSD) activity. The protein expression of the three cytochrome P450s (CYP11A1, CYP19A1, and CYP21A2) is involved in the steroidogenesis. The levels of testosterone (T) and estradiol (E2) were also determined in the plasma of N-nitrosamines-treated rabbits after one, four-, eight- and twelve weeks of treatment of male New Zealand rabbits with an oral dose of 0.5 mg/kg B.W/day of each compound. In addition, activities of glutathione reductase (GR), superoxide dismutase (SOD), catalase (CAT) and levels of free radicals measured as thiobarbituric acid reactive substances (TBARS), and reduced glutathione (GSH) level were quantified in both livers and testes. The present study showed that levels of free radicals (TBARS) were markedly increased, whereas GSH levels were depleted in the tissues of both livers and testes after treatment of rabbits with any of N-nitrosamines. In addition, all tested N-nitrosamines inhibited the activities of antioxidant enzyme activities (GR, GST, SOD, and CAT) in hepatic and testicular tissues of rabbits after 12 weeks of treatment. Histopathological examination showed that N-nitrosamines caused lymphocytic infiltration with vascular degeneration and necrosis, congestion of central vein with RBCs hemolysis, dilated sinusoids, as well as fibrosis around portal areas were seen in hepatic tissues. In the testes, histopathological examination displayed disorganized seminiferous tubules with degeneration of germinal epithelium and Sertoli cells. Also, spermatogenic cells had pyknotic nuclei and others were detached from basement membranes of seminiferous tubules, edema was seen between seminiferous tubules. Moreover, the present data showed that MEN and DEN down-regulated the protein expression of both CYP19A1 and 21A2 in both livers and testes of male rabbits. In addition, both MEN and DEN decreased levels of testosterone and estradiol in plasma of treated rabbits. On the one hand, DMN and DPN markedly up-regulated the protein expression of CYP19A1 in both hepatic and testicular tissues of treated rabbits. These compounds potentially increased estradiol and decreased testosterone levels. On the other hand, no correlation was found between the expression of CYP11A1 and levels of both testosterone and estradiol. It is concluded that most of tested N-nitrosamines induce different changes, whic...

Mutations in the genes encoding enzymes involved in the metabolism of chemical carcinogens can significantly affect the risk of cell transformation and cancer development. The resident Lebanese population has experienced a sharp increase in cancer incidence within the last few years. The relationship between gene polymorphisms of metabolic enzymes and gastrointestinal (GI) cancer incidence was not previously investigated. The aim of this study was to investigate the relationship between CYP1A1, CYP2E1, and GSTM1 gene polymorphisms and GI cancer incidence among Lebanese. Blood and/or paraffin-embedded biopsy samples were collected from patients and healthy controls. The genotypes were determined by polymerase chain reaction and polymerase chain reaction-restriction fragment length polymorphism. The results of the present case-control study show that the studied Lebanese population generally resembles Caucasian populations with respect to the considered polymorphisms. Further, the GSTM1*0/*0 genotype is a significant risk factor for gastric (odds ratio = 4.1; 95% confidence interval: 1.2-14.5) and colorectal cancers (odds ratio = 3.8; 95% confidence interval: 1.7-8.5); on the other hand, CYP1A1*2A and CYP2E1*6 alone are not significantly associated with GI cancer development, although CYP1A1*2A was more frequent among patients. A remarkable and statistically significant 36.5-fold increase in the risk of gastric cancer was observed among patients with CYP1A1*2A/*2A combined with GSTM1*0/*0. The investigation of genetic risk factors and susceptibility gene polymorphisms in Lebanese is helpful for better understanding of GI cancer etiology.

A wide variety of natural products have powerful chemopreventive effects due to their antioxidant, antimutagenic, and anti-inflammatory activities that enable them to arrest cell proliferation in several cancer models. In the present study, we shed light on the protective mechanism of Nigella sativa extract against diethylnitrosamine (DENA)-induced preneoplastic stage of hepatocellular carcinoma (HCC) in rats. We studied the extract effect on EGFR/ERK1/2 signaling pathway as one of the major signaling pathways controlling cell proliferation during hepatocarcinogenesis as well as the investigation of its antioxidant activity. The study also compared the effects of NSEE to those of (thymoquinone) TQ and silymarin as hepatoprotective substances. Rats received daily doses of NSEE (150, 250, 350 mg/kg BW), a dose per three alternative days/week of TQ (20 mg/kg BW) and a daily dose of silymarin (100 mg/kg BW). The doses were administered orally by gavage for 12 days before DENA and CCl administration, and then the supply of NSEE, TQ or silymarin was continued until the end of the experiment (16 weeks). DENA administration activated EGFR/ERK1/2 signaling and caused a significant increase in P-EGFR and P-ERK1/2 as well as a significant up-regulation of expression of target genes such as PCNA, c-fos and Bcl2, which indicated the increase in cell proliferation. Furthermore, a significant elevation in alpha-fetoprotein (AFP) and hepatic enzymes was observed in DENA-treated rats in addition to a decrease in the antioxidant status. The protection with NSEE, TQ, or silymarin has the potential to inhibit the EGFR/ERK1/2 activation and improve the antioxidant status. Moreover, the action of NSEE against the hepatocarcinogenesis was supported by high antioxidant activity and the histopathological observations of the liver. These data suggest that NSEE has a chemopreventive role in DENA-induced HCC through the inhibition of the EGFR/ERK1/2 signaling pathway and their target genes in addition to its role as an antioxidant.

The levels of arylsulfatases A and B, α-amylase, aspartate transcarbamylase, and γ-glutamyl transpeptidase were investigated during the infection of mice with schistosoma mansoni. This infection caused a significant (p<0.001) increase in the activity of hepatic arylsulfatase B (ASB), aspartate transcarbamylases and γ-glutamyl transpeptidase. A non-significant difference occurred for α-amylase (p<0.3) and arylsulfatase A (p>0.5) when compared to the control. The specific activity of hepatic ASB was progressively increased with the progression of the Schistosoma-infection. Moreover, the kinetic studies of hepatic ASB in Schistosomainfection showed that a slight decrease in the value of K m and about a 40% increase in V max when compared to the control. In addition, the pH optimum of hepatic ASB was altered from 6 to 7 as a result of schistosomiasis. These observations suggest that there are schistosomiasis-associated changes of the catalytic and kinetic properties of hepatic ASB.

The aim of the present study was to evaluate the diagnostic relevance of urinary fibronectin (FN), telomerase (RTA), and cytokeratin 20 (CK20) mRNA in comparison with voided urine cytology (VUC). The study included 132 patients with bladder cancer, 60 patients with benign bladder lesions, and 48 healthy individuals. All were subjected to urine cytology, estimation of fibronectin by ELISA, RTA by TRAP, and CK20 mRNA by conventional RT-PCR in urothelial cells from voided urine. The best cutoff point for FN was determined by receiver operating characteristic curve (41.7 ng/mg protein) revealed the highest sensitivity for malignant (80%) followed by the benign (70%) than the healthy individuals (4.1%) at P < 0.001. Also, RTA and VUC showed significant difference among the three investigated groups (P < 0.001). The overall sensitivity (89.3%) and specificity (98.4%) were the highest for CK20 mRNA. Combined sensitivity of VUC with FN, RTA, and CK20 mRNA together (98.4%) was higher than either the combined sensitivity of VUC with any of them or than that of the biomarker alone. Accordingly, when the diagnostic efficacy was considered, CK20 mRNA had the highest sensitivity and specificity compared to all investigated markers.